APOE4 -disrupted intracellular lipid homeostasis in human and yeast cells was reversed by promoting phospholipid synthesis through choline supplementation.

The ε4 allele of apolipoprotein E (APOE4) is a genetic risk factor for many diseases, including late-onset Alzheimer's disease (AD). We investigate the cellular consequences of APOE4 in human iPSC-derived astrocytes, observing an endocytic defect in APOE4 astrocytes compared with their isogenic APOE3 counterparts. Given the evolutionarily conserved nature of endocytosis, we built a yeast model to identify genetic modifiers of the endocytic defect associated with APOE4. In yeast, only the expression of APOE4 results in dose-dependent defects in both endocytosis and growth. We discover that increasing expression of the early endocytic adaptor protein Yap1802p, a homolog of the human AD risk factor PICALM, rescues the APOE4-induced endocytic defect. In iPSC-derived human astrocytes, increasing expression of PICALM similarly reverses endocytic disruptions. Our work identifies a functional interaction between two AD genetic risk factors-APOE4 and PICALM-centered on the conserved biological process of endocytosis.

Transient receptor potential (TRP) proteins have been implicated in several cell functions as non-selective cation channels, with about 30 different mammalian TRP channels having been recognized. Among them, TRP-melastatin 2 (TRPM2) is particularly involved in the response to oxidative stress and inflammation, while its activity depends on the presence of intracellular calcium (Ca²⁺). TRPM2 is involved in several physiological and pathological processes in the brain through the modulation of multiple signaling pathways. The aim of the present review is to provide a brief summary of the current insights of TRPM2 role in health and disease to focalize our attention on future potential neuroprotective strategies.

Amyloid beta (Aβ)-induced abnormal neuroinflammation is recognized as a major pathological feature of Alzheimer’s disease (AD), which results in memory impairment. Research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease, or it is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, are crucial components of the innate immune system and are usually activated in response to infection or tissue damage. Although inflammasome activation plays critical roles against various pathogens in host defense, overactivation of inflammasome contributes to the pathogenesis of inflammatory diseases, including acute central nervous system (CNS) injuries and chronic neurodegenerative diseases, such as AD. This review summarizes the current literature on the role of the NLRP3 inflammasome in the pathogenesis of AD, and its involvement in infections, particularly SARS-CoV-2. NLRP3 might represent the crossroad between the hypothesized neurodegeneration and the primary COVID-19 infection.

Alzheimer’s disease (AD) is the most common form of dementia among older people. Although soluble amyloid species are recognized triggers of the disease, no therapeutic approach is able to stop it. 6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a major bioactive compound in Wasabia japonica, which is a typical Japanese pungent spice. Recently, in vivo and in vitro studies demonstrated that 6-MSITC has several biological properties. The aim of the present study was to investigate the neuroprotective activity of 6-MSITC in a murine AD model, induced by intracerebroventricular injection of β-amyloid oligomers (Aβ_1-42O). The treatment with 6-MSITC started 1 h after the surgery for the next 10 days. Behavioral analysis showed that 6-MSITC ameliorated Aβ_1-42O-induced memory impairments. The decrease of glutathione levels and increase of reactive oxygen species in hippocampal tissues following Aβ_1-42O injection were reduced by 6-MSITC. Moreover, activation of caspases, increase of inflammatory factors, and phosphorylation of ERK and GSK3 were inhibited by 6-MSITC. These results highlighted an interesting neuroprotective activity of 6-MSITC, which was able to restore a physiological oxidative status, interfere positively with Nrf2-pathway, decrease apoptosis and neuroinflammation and contribute to behavioral recovery. Taken together, these findings demonstrated that 6-MSITC could be a promising complement for AD therapy.

Sulforaphane (SFN), an isothiocyanate (ITC) derived from cruciferous vegetables, particularly broccoli and broccoli sprouts, has been widely investigated due to its promising health-promoting properties in disease, and low toxicity in normal tissue. Although not yet fully understood, many mechanisms of anticancer activity at each step of cancer development have been attributed to this ITC. Given the promising data available regarding SFN, this review aimed to provide an overview on the potential activities of SFN related to the cellular mechanisms involved in glioblastoma (GBM) progression. GBM is the most frequent malignant brain tumor among adults and is currently an incurable disease due mostly to its highly invasive phenotype, and the poor efficacy of the available therapies. Despite all efforts, the median overall survival of GBM patients remains approximately 1.5 years under therapy. Therefore, there is an urgent need to provide support for translating the progress in understanding the molecular background of GBM into more complex, but promising therapeutic strategies, in which SFN may find a leading role.